Abstract
Ceramide and sphingosine are important interconvertible sphingolipid metabolites which govern various signaling pathways related to different aspects of cell survival and senescence. The conversion of ceramide into sphingosine is mediated by ceramidases. Altogether, five human ceramidases—named acid ceramidase, neutral ceramidase, alkaline ceramidase 1, alkaline ceramidase 2, and alkaline ceramidase 3—have been identified as having maximal activities in acidic, neutral, and alkaline environments, respectively. All five ceramidases have received increased attention for their implications in various diseases, including cancer, Alzheimer’s disease, and Farber disease. Furthermore, the potential anti-inflammatory and anti-apoptotic effects of ceramidases in host cells exposed to pathogenic bacteria and viruses have also been demonstrated. While ceramidases have been a subject of study in recent decades, our knowledge of their pathophysiology remains limited. Thus, this review provides a critical evaluation and interpretive analysis of existing literature on the role of acid, neutral, and alkaline ceramidases in relation to human health and various diseases, including cancer, neurodegenerative diseases, and infectious diseases. In addition, the essential impact of ceramidases on tissue regeneration, as well as their usefulness in enzyme replacement therapy, is also discussed.
Highlights
Ceramides are bioactive sphingolipids responsible for cell apoptosis, senescence, and autophagy [1]
The activation of acid ceramidase (ACDase) induces a pro-survival state, while its inhibition leads to cell death through a variety of apoptotic pathways mediated by caspases (CASP), poly polymerase (PARP), or cathepsins (CTS) [10,17,18,19,20,21,22,23,24,25]
It was demonstrated that the activity of ACDase was significantly inhibited by Carmofur [55,58], LCL521 [19,65,69,70], Ceranib2 [24,71,72,73], N-oleocylethanolamine (NOE) [22,57], ARN14988 [74], LCL204 [10,64], Monascus Purperus (MP) [18], Hesperetin (Hst) [17], Hesperetine-7-O-acetate (HTA) [17], Silibinin [20], Curcumin [23], and Sanguinarine [21,75], leading to an increased accumulation of intracellular ceramide and apoptosis in various types of cancer cells, including glioblastoma; squamous cell carcinoma; acute myeloid leukemia; colorectal adenocarcinoma; and breast, prostate, lung, gastric, and kidney cancer
Summary
Ceramides are bioactive sphingolipids responsible for cell apoptosis, senescence, and autophagy [1]. The removal ceramidase-based enzyme replacement therapy that simultaneously achieves ceramide reduction of two hydrogens from a fatty acid chain of the dihydroceramides by the enzyme desaturase results in and SPH elevation has been recently examined [4]. This therapeutic approach intends to reduce the the formation of ceramides (Figure 1) [2]. SPH is the most common sphingolipid base molecule in ceramidases have been identified and classified according to their optimal pH for catalytic activity: mammalian cells and is(ACDase) the precursor of S1P one acid ceramidase encoded by[1]. Is18:0 ubiquitously expressed tissues, with a high tissues, with a high expression in the heart and kidneys and is known for its role expression in the heart and kidneys and is known for its role in senescence and apoptosis [7]. in senescence and apoptosis [7]
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